Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses

Nadia Alatrakchi, Camilla S Graham, Hans J J van der Vliet, Kenneth E Sherman, Mark A Exley, Margaret James Koziel

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Hepatitis C virus (HCV)-specific T-cell responses are rarely detected in peripheral blood, especially in the presence of human immunodeficiency virus (HIV) coinfection. Based on recent evidence that T-regulatory cells may be increased in chronic HCV, we hypothesized that functional blockade of regulatory cells could raise HCV-specific responses and might be differentially regulated in the setting of HIV coinfection. Three groups of subjects were studied: HCV monoinfected, HCV-HIV coinfected, and healthy controls. Frequencies of peripheral T cells specific for peptides derived from HCV core, HIV type 1 p24, and recall antigens were analyzed by gamma interferon (IFN-gamma) enzyme-linked immuno-spot assay. HCV-specific T-cell responses were very weak in groups with HCV and HCV-HIV infections. Addition of blocking antibodies against transforming growth factor beta1 (TGF-beta1), -2, and -3 and interleukin-10 specifically increased the HCV-specific T-cell responses in both infected groups; however, this increase was attenuated in the group with HCV-HIV coinfection compared to HCV infection alone. No increase in recall antigen- or HIV-specific responses was observed. Flow cytometric sorter analysis demonstrated that regulatory-associated cytokines were produced by HCV-specific CD3(+)CD8(+)CD25(-) cells. Enhancement of the IFN-gamma effect was observed for both CD4 and CD8 T cells and was mediated primarily by TGF-beta1, -2, and -3 neutralization. In conclusion, blockade of TGF-beta secretion could enhance peripheral HCV-specific T-cell responses even in the presence of HIV coinfection.

Original languageEnglish
Pages (from-to)5882-92
Number of pages11
JournalJournal of Virology
Issue number11
Publication statusPublished - Jun 2007
Externally publishedYes

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